The field of the invention is cytokine-mediated therapeutics.
An effective immune response begins when an antigen or mitogen triggers the activation of T cells. In the process of T cell activation, numerous cellular changes occur, which include the expression of cytokines and cytokine receptors. One of the cytokines involved in the immune response is interleukin-15 (IL-15). IL-15 is a T cell growth factor that stimulates the proliferation and differentiation of B cells, T cells, natural killer (NK) cells, and lymphocyte-activated killer (LAK) cells in vitro. In vivo, the proliferation of these cell types enhances the immune response.
IL-15 binds to a heterotrimeric receptor that consists of the IL-2Rxcex2 subunit, the IL-2Rxcex3 subunit, and a unique IL-15Rxcex1 subunit.
Patients benefit from suppression of the immune response in a number of circumstances, for example, in the event of organ transplantation or autoimmune disease. In other circumstances, for example when select immune cells have become malignant or autoaggressive, it is beneficial to actively destroy them.
The invention features mutants of the cytokine IL-15. Preferably, these mutants bind the IL-15 receptor complex with an affinity similar to wild-type IL-15, but fail to activate signal transduction. The mutant polypeptides of the invention therefore compete effectively with wild-type IL-15 and, when they do so, they block one or more of the events that normally occur in response to IL-15 signalling, such as cellular proliferation. By modulating the events mediated by the IL-15 receptor complex, mutant IL-15 polypeptides can modulate the immune response, and thus are therapeutically useful.
Mutant IL-15 polypeptides can have several characteristics that are advantageous in the context of treatment regimes. First, they are unlikely to be immunogenic because they can differ from wild type IL-15 by only a few substituted residues. Second, IL-15 mutants can bind IL-15Rxcex1 with the same high affinity as wild type IL-15 and thus, can compete effectively for the receptor. Third, IL-15 mutants can be easily modified to remain active in the circulation for a prolonged period of time, or to produce a lytic response in cells to which they bind. In addition, the IL-15 receptor alpha (IL-15Rxcex1) polypeptide is expressed by activated or malignant immune cells, but not on resting immune cells. Thus, the mutant polypeptide of the invention can be used to specifically target activated or malignant immune cells.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. Although materials and methods similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred materials and methods are described below.